For decades, fluorouracil (FU) was the sole active agent. This has changed markedly since the year 2000, with the approval of irinotecan, oxaliplatin, three humanized monoclonal antibodies (MoAbs) that target the vascular endothelial growth factor (VEGF; bevacizumab) and epidermal growth factor receptor (EGFR; cetuximab and panitumumab), intravenous aflibercept, a recombinant fusion protein consisting of VEGF binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2, and 3) as well as several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes, and trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. The best way to combine and sequence these agents is still not established. Most recently, the immune checkpoint inhibitors pembrolizumab and nivolumab have been approved for advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) CRC that has progressed following conventional chemotherapy.

The best way to combine and sequence all of these agents is not known. Increasingly, biomarker expression is driving therapeutic decision-making. However, the biologic targets for most of the agents that are active against metastatic CRC are unknown, with the exception of agents targeting the EGFR and immunotherapy with immune checkpoint inhibitors:

●Benefit from MoAbs targeting the EGFR is restricted to patients whose tumors do not contain mutated RAS genes or a mutation in the BRAF gene at the 600 codon (V600E mutation).

●Benefit from immunotherapy with immune checkpoint inhibitors appears to be limited to the subset of tumors that are MSI-H or dMMR.

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